Age-related macular degeneration (AMD) is the leading cause of blindness in older adults. The neovascular form of the disease (NVAMD) is primarily responsible for severe vision loss. Current NVAMD treatments involve repeated intraocular injections of biologics that neutralize vascular endothelial growth factor (VEGF), an important neovascular (NV) stimulus. Aflibercept (Eylea(R)), approved in late 2011, provides an incremental benefit over ranibizumab (Lucentis(R)) and bevacizumab (Avastin(R)), as it reduces injection frequency to every 2 months, from the monthly treatment regimen recommended for the other anti-VEGF agents. However, intraocular injection frequencies of 6-12 times a year remain a major burden on patients and health care providers. Through the screening of over 10,000 compounds, we have identified small molecules that are highly neuroprotective of cultured primary retinal ganglion cells. One of these compounds, FDA-approved for an unrelated indication, also displays anti-angiogenic activity. Using this intriguing compound as our basis, we have generated a structural analogue through medicinal chemistry that preserves the neuroprotective function and is expected to retain the anti-angiogenic activity of its parent compound. GrayBug has developed a proprietary microparticle ocular drug delivery system that, following intravitreal administration, allows controlled release and sustained localized delivery t the eye, without causing significant inflammation. Here, we combine our microparticle delivery system with promising anti-angiogenic and neuroprotective drugs to develop a new controlled release therapeutic for the treatment of NVAMD. The ultimate goal is to develop a product with a duration of effect sustained for >3 months therefore requiring only 3-4 treatments per year in NVAMD patients. In preliminary rodent studies, intravitreal administration of the GrayBug drug-releasing microparticles caused a significant reduction of choroidal NV (CNV) sustained for at least 9 weeks. As loss of neuroprotection is a hallmark of both NVAMD and dry AMD thus, a sustained-release formation of a small molecule drug that confers both anti-angiogenic and neuroprotective activities represents a significant treatment advance. In Aim 1, we will generate and characterize microparticles that release the drugs continuously over a sustained period. Microparticles that encapsulate the agents will be produced using the proprietary GrayBug technology exclusively licensed from Johns Hopkins University (JHU). Similar microparticles produced using this technology were noninflammatory when delivered intracamerally to rabbits, an extremely sensitive evaluation model. The drug-releasing particles will be characterized fully and the duration of drug release in vitro will be evaluated. In Aim 2, we will evaluate the antiangiogenic activity of the drug-releasing microparticles in a murine CNV model. Both suppression of new NV and regression of pre- existing pathological NV will be evaluated. In Aim 3, the duration of drug release in the rabbit eye will be evaluated over a period of three months and preliminary safety analyses will be performed. Safety evaluations include fundus exams and retinal morphology analyses to assess the long-term effects of drug exposure to the eye. The demonstration of efficacy in the murine CNV model combined with sustained drug release in the rabbit eye, would provide evidence of the therapeutic potential of our drug delivery strategy for the treatment of NVAMD. Successful completion of these specific aims will lead us to Phase II studies and ultimately to human clinical evaluation.